5Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands

Corresponding author: Barbara M. Schulte, b.schulte{at}ncmls.ru.nl.

Abstract

Enteroviruses of the human enterovirus B species (HEV-Bs) (e.g., coxsackie B viruses [CVBs] and echoviruses) have been implicated
as environmental factors that trigger/accelerate type 1 diabetes, but the underlying mechanism remains elusive. The aim of
this study was to gain insight into the cytokines and chemokines that are produced by human pancreatic islets upon infection
with CVBs. To this end, we studied the response of human islets of Langerhans upon mock or CVB3 infection. Using quantitative
PCR, we showed that upon CVB3 infection, transcription of interferon (IFN), IFN-stimulated genes, and inflammatory genes was
induced. Analysis of secreted cytokines and chemokines by Luminex technology confirmed production and secretion of proinflammatory
cytokines (e.g., interleukin [IL]-6 and tumor necrosis factor-α) as well as various chemotactic proteins, such as IFN-γ–induced
protein 10, macrophage inflammatory protein (MIP)-1α, MIP-1β, and IL-8. Infection with other HEV-Bs induced similar responses,
yet their extent depended on replication efficiency. Ultra violet–inactivated CVB3 did not induce any response, suggesting
that virus replication is a prerequisite for antiviral responses. Our data represent the first comprehensive overview of inflammatory
mediators that are secreted by human islets of Langerhans upon CVB infection and may shed light on the role of enteroviruses
in type 1 diabetes pathogenesis.